Cannabidiol and Sodium Channel Pharmacology: General Overview, Mechanism, and Clinical Implications

Figures

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  Figure 1.. An illustration of the primary structure of the α-subunit of voltage-gated sodium (Nav) channels. At the top of the figure, we show a cartoon of the Nav channel structure. At the bottom we show top and side views of the Nav1.5 (PDB ID: 6UZ3). The cartoon and structure are color-coded.

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  Figure 2.. Types of voltage-gated sodium (Nav) currents. This cartoon illustrates the types of Nav currents described in the text. (1) The zero-sodium current condition, in which the Nav channel is in the resting state. (2) The maximal peak sodium current. (3) The fast inactivated state (Note that fast inactivation proceeds through an allosteric process, as described in the main text. The ball and chain cartoon here is only meant to illustrate the competition between the fast inactivation particle and β4, indicating two populations of channels, one bound with IFMT (isoleucine-phenylalanine-methionine-threonine) and the other with β4. (4) The β4 subunit in its bound form, thereby blocking sodium currents. (5) The unbinding of β4 causes a surge of inward sodium current. As mentioned in the text, recent findings suggest that β4 may not be necessary for resurgent current generation (White and others 2019). (6) Channels fast inactivate.

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  Figure 3.. Binding of pore domain (PD) blockers on the outer and inner segments. In the middle of both structures, we show a dashed line which is meant to illustrate a division between the extracellular funnel and selectivity filter, and central cavity and activation gate. (a) The binding of tetrodotoxin (TTX) to the outer PD (more rigid part of the domain, from PDB ID: 6UZ3). (b) A view of Nav1.5 and flecainide (PDB ID: 6UZ3).

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  Figure 4.. Voltage-gated sodium (Nav) channel distribution. This is a cartoon illustrating the predominantly tissue-specific distribution of Nav channels in the human body, along with general hyperexcitability conditions that are caused by mutations in each category.

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  Figure 5.. Cannabidiol (CBD) binding pose inside voltage-gated sodium (Nav) channels. (a-c) The crystallized binding of CBD inside the bacterial NavMs (PDB ID: 6YZ0). (d, e) The docked pose of CBD inside the human Nav1.4 structure (PDB ID: 6AGF). The poses are in close agreement.

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  Figure 6.. Proposed channel blocking scheme for an ultra-hydrophobic compound. Hypothesis for block by local anesthetics (LAs) (based on Hille 1977, 2001; Hondeghem and Katzung 1977). (a, b) The first two models are based on previous studies. (a) Voltage-gated sodium (Nav) states and transitions with charged drug molecules. Charged (hydrophilic) drug may come and go only while the gate is open. (b) Neutral (hydrophobic) drug can bind and unbind even if when the gate is closed. Therefore, two pathways exist for drug to reach its receptor in the pore. The hydrophilic pathway is closed when the gate is closed. (c) The third model is based on our results from our studies on CBD and Nav channels. The star indicates drug. We propose as the drug becomes more hydrophobic, its interaction with the channel transitions from only the open-state (O) to only interactions with rest (R) and inactivated (I) states.

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  Figure 7.. Cannabidiol (CBD) pathway and effect on excitability. (a) The pathway of CBD from the lipid phase through the voltage-gated sodium (Nav) fenestration and into the pore, where it interacts to some extent by the local anesthetic (LA) site F or T residues, depending on the Nav channel. (b) CBD blocking generic peak, persistent, and resurgent sodium currents. (c) The general effect CBD on a generic action potential morphology.